Key result
Cardiac-targeted overexpression of the alpha(1A)-adrenergic receptor in transgenic mice induced an 80% increase in cardiac contractility (dP/dt(max), P<0.0001) without causing left ventricular hypertrophy.
Why the study?
Does cardiac-targeted overexpression of the alpha(1A)-adrenergic receptor enhance cardiac contractility or induce hypertrophy in transgenic mice?
Does cardiac-targeted overexpression of the alpha(1A)-adrenergic receptor enhance cardiac contractility or induce hypertrophy in transgenic mice?
p-value: p=<0.0001
Cardiac-targeted overexpression of the alpha(1A)-adrenergic receptor in mice enhances cardiac contractility without inducing pathological hypertrophy, providing the first in vivo evidence for its inotropic action.
α1A-AR overexpression boosts contractility without hypertrophy in mice; hypothesis-generating, leaves open human translation.
Activation of the alpha(1A)-adrenergic receptor (alpha(1A)-AR)/Gq pathway has been implicated as a critical trigger for the development of cardiac hypertrophy. However, direct evidence from in vivo studies is still lacking. To address this issue, transgenic mice with cardiac-targeted overexpression of the alpha(1A)-AR (4- to 170-fold) were generated, using the rodent alpha-myosin heavy chain promoter. Heterozygous animals displayed marked enhancement of cardiac contractility, evident from increases in dP/dt(max) (80%, P<0.0001), dP/dt(max)/LVP(inst) (76%, P<0.001), dP/dt(max):dP/dt(min) (104%, P<0.0001), and fractional shortening (33%, P<0.05). Moreover, changes in the dP/dt(max)-end-diastolic volume relationship provided load-independent evidence of a primary increase in contractility. Blood pressure and heart rate were largely unchanged, and there was a small increase in (-)norepinephrine-stimulated, but not basal, phospholipase C activity. Increased contractility was directly related to the level of receptor overexpression and could be completely reversed by acute alpha(1A)- but not beta-AR blockade. Despite the robust changes in contractility, transgenic animals displayed no morphological, histological, or echocardiographic evidence of left ventricular hypertrophy. In addition, apart from an increase in atrial natriuretic factor mRNA, expression of other hypertrophy-associated genes was unchanged. To our knowledge, these data provide the first in vivo evidence for an inotropic action of the alpha(1A)-AR.
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Lin et al. (2001) studied Cardiac contractility and hypertrophy. Cardiac-targeted overexpression of the alpha(1A)-adrenergic receptor vs. Control mice was evaluated on Cardiac contractility (dP/dt(max)) (p=<0.0001). Cardiac-targeted overexpression of the alpha(1A)-adrenergic receptor in transgenic mice induced an 80% increase in cardiac contractility (dP/dt(max), P<0.0001) without causing left ventricular hypertrophy.
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